Neonatal Respiratory Distress Panel

Neonatal Respiratory Distress syndrome (RDS) is a relatively common breathing disorder that affects newborns. RDS occurs most often in preterm neonates. Less often, RDS can affect full term newborns. As the most common cause of respiratory distress in premature infants, RDS occurs in about 24,000 infants born in the United States annually. RDS is caused by a lack of surfactant, which is a foamy substance that helps the lungs fill with air and keeps the air sacs from deflating. Without enough surfactant, the lungs collapse and the newborn has difficulty in breathing. Symptoms include expiratory grunting, rapid and shallow breathing, sharp pulling inward of the muscles between the ribs when breathing, nasal flaring, cyanosis and apnea. RDS usually happens in the first 24 hours after birth, potentially requiring mechanical ventilation or positive end-expiratory pressure (PEEP) (Yadav et al. 2020. PubMed ID: 32809614).

Pathogenic variants in the ABCA3, SFTPB, SFTPC, NKX2-1 and FOXF1 genes have been reported to be causative for pulmonary epithelial cell and surfactant dysfunction (Somaschini et al. 2018. PubMed ID: 29255193; Thorwarth et al. 2014. PubMed ID: 24714694; Pradhan et al. 2019. PubMed ID: 31199666). Surfactant protein (SP-B) deficiency (SFTPB) and ABCA3-related surfactant deficiency (ABCAD3) present as severe and often fatal lung disease in neonates. Surfactant protein (SP-C) deficiency (SFTPC) can present with chronic interstitial lung disease (ILD) in term newborns, children and adults, with a small percentage present with neonatal respiratory distress. RDS is a common symptom in NKX2-1-related disorders, and patients may also have choreoathetosis and congenital hypothyroidis. Pathogenic variants in FOXF1 cause congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), and infants with ACDMPV often develop respiratory distress with persistent pulmonary hypertension.

Genetic testing is helpful in the differential diagnosis of genetic-related surfactant deficiency from developmental surfactant deficiencies, generalized or localized infection, cardiac disorders with obstructed pulmonary venous return, and other respiratory distress syndromes (Hamvas. 2006. PubMed ID: 17142157).

While prematurity is a major cause of RDS, neonatal RDS can also be due to genetic abnormalities with lung development. RDS may be inherited in an autosomal recessive manner through pathogenic variants in the ABCA3 or SFTPB genes, and an autosomal dominant manner through pathogenic variants in the SFTPC, NKX2-1and FOXF1 genes (Hamvas. 2006. PubMed ID: 17142157). A wide range of genetic variants, including missense, nonsense, splicing variants, small deletions/insertions, and exonic deletions have been reported in all these genes. De novo variants were frequently found in SFTPC, NKX2-1 and FOXF1 genes (Somaschini et al. 2018. PubMed ID: 29255193; Thorwarth et al. 2014. PubMed ID:24714694; Pradhan et al. 2019. PubMed ID: 31199666).

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

In a study of 337 infants with severe respiratory disease, 20.5% were reported to have pathogenic variants in the SFTPB (14%), ABCA3 (4.7%) or SFTPC (1.8%) genes (Shulenin et al. 2004. PubMed ID: 15044640). In a study of 101 probands with choreoathetosis, congenital hypothyroidism, neonatal respiratory distress syndrome, 27 patients were found to have NKX2-1 pathogenic variants, including 17 point mutations (~17%) and 10 deletions (~10%) (Thorwarth et al. 2014. PubMed ID: 24714694). Pathogenic variants in FOXF1 were reported in 70%-96% of patients with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (Sen et al. 2013. PubMed ID: 23505205; Pradhan et al. 2019. PubMed ID: 31199666).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).